Chemotherapy alters thrombomodulin and factor VIIIc expression resulting in acquired activated protein C resistance and enhanced thrombin generation in cancer associated thrombosis

Background: Tumour type, treatment and patient related factors contribute to cancer associated venous thromboembolism (VTE), however, the role of each factor and the mechanisms involved are not understood.

Aim: To assess the role of the tumour, and of chemotherapy, in mediating the procoagulant response associated with VTE in gynaecological cancer patients.

Methods: Gynaecological cancer patients who developed VTE during follow-up (n = 59) (VTE+) were matched with treatment naïve(treatment (-)(VTE-)(n = 120) and chemotherapy treated patients(treatment (+)(VTE-) (n = 57)). Thrombin generation, Factor V(FV), VIIIc(FVIIIc), Tissue Factor Pathway Inhibitor(TFPI), soluble Thrombomodulin(sTM), Protein S(PS), C(PC) endothelial protein C receptor(EPCR) and fibrinogen were compared in each group. EPCR and TM expression was assessed in EA.hy926 cells in vitro following addition of chemotherapy agents. mRNA expression of coagulation genes was measured in tumour biopsies.

Results: Thrombin generation was increased in treatment(-)VTE(+) compared with treatment(-)VTE(-) controls but not in the treatment(+)VTE(+) patients. Using the TM modified assay, thrombin generation was increased in the treatment (+)VTE(-) group compared with treatment(-)(VTE-) with a further increase in the treatment (+) VTE(+) group. Reduced levels of sTM in treatment (+) VTE(+) patients correlated with thrombin generation. TM expression was reduced in vitro by carboplatin and paclitaxel. FVIIIc was increased in both VTE groups and was predictive of VTE. F5 mRNA levels were lower in tumours from VTE(+) patients compared with controls.

Conclusion: Chemotherapy alters sTM and confers an acquired activated Protein C(aPC) resistance which may be implicated in cancer associated VTE in gynaecological cancer patients. FVIIIc may be a useful predictive marker for VTE in cancer patients in this setting.